Project Summary/Abstract Heart failure with preserved ejection fraction (HFpEF) is perhaps the most common ?untreatable? disease in the world. It makes up more than 50% of all heart failure cases and in contrast to other cardiovascular diseases, its prevalence is increasing resulting in substantial morbidity, mortality, and cost. HFpEF has been resistant to ?one-size-fits-all? therapies that have become standard treatment of heart failure with a reduced ejection fraction (HFrEF); therefore there has been increasing pressure to better phenotype this complex and multifactorial disease in order to direct ?personalized? pathophysiology based therapy. The dominant symptom of patients with HFpEF is exercise intolerance and dyspnea on exertion (DOE). Such dyspnea can be pro- found, occur at very low levels of external work, and thereby limits physical activity leading to a downward spiral of inactivity and deconditioning which compounds the underlying cardiac and vascular disease. In 2012 The National Heart, Lung, and Blood Institute convened a working group to identify the key knowledge gaps in this field and to suggest strategies for future research on exercise intolerance, and exercise training as a treat- ment for heart failure.(Fleg 2015) We propose to address each of the working group recommendations through a unique PPG that links 4 projects and 3 cores to address the global objective of determining the mechanisms of exercise intolerance and dyspnea in patients with HFpEF and based on this pathophysiology, designing cre- ative exercise interventions that improve quality of life. Although virtually all Program Project Grants are linked together by a common theme, this PPG will be unique in that the individual projects will be linked even more closely by working together on common patients. All patients will be recruited into the Program by a specializ- ed Recruitment Core; each patient will then undergo high resolution physiological phenotyping by all 4 projects followed by a tailored intervention designed to test the clinical relevance of the phenotyping strategy. This approach will allow us to accomplish the following specific aims: Specific Aim 1: To determine the mechan- ism(s) of exercise intolerance and DOE in patients with HFpEF using invasive and non-invasive cardio- pulmonary exercise testing. Patients will be divided into those with a primarily ?central? limitation and those with a primarily ?peripheral limitation? based on this initial assessment. Specific Aim #2: to determine whether a ?precision? exercise intervention based on the high resolution phenotyping will lead to clinically meaningful improvements in functional capacity and reduction in dyspnea. All patients will be randomized to undergo one of two tailored exercise interventions for 16 weeks: a) small muscle mass, single leg kicking exercise to allow high intensity muscle exercise without challenging cardiovascular reserve; b) reduce cardiac filling pressure during exercise with acute ingestion of TNG to allow higher systemic workloads and improved training. By combining efforts into a PPG integrated by studying the same patients across multiple platforms, our team has the potential to make highly novel advances towards improving the quality of life for patients with HFpEF.